Alexander Nott, Ph.D - Project Scientist
Department of Cellular & Molecular Medicine
University of California, San Diego
Dec 09, 2019 @ 9:30 a.m.
Long-lasting changes in gene expression are mediated by ‘epigenetic’ adaptations in chromatin structure; these modifications orchestrate gene expression programs that guide cell-type-specific responses to environmental signals. My research explores how cell-type-specific epigenetic mechanisms drive brain physiology in health and disease. My early work demonstrated that histone deacetylase 2 (HDAC2), an epigenetic eraser, is negatively regulated by nitric oxide signaling in primary neurons. Further, I showed that nitric oxide-mediated inhibition of HDAC2 is required for activation of gene expression programs critical for normal mouse brain development. Next, I studied Rett syndrome, a brain disorder caused by mutations in MeCP2. I found that neuronal loss of HDAC3, a binding partner of MeCP2, elicits Rett syndrome-associated behaviors in mice. Contrary to the idea that HDAC3 functions as an epigenetic eraser, I found that HDAC3 activated gene expression through regulation of the FOXO transcription factors. My current research explores the function of noncoding DNA variants associated with brain-related disease-risk at gene regulatory regions called enhancers. I generated promoter-enhancer interactome maps that connect noncoding disease-risk variants to target genes in the major cell types of the brain. These datasets revealed that genetic variants associated with increased risk of Alzheimer’s disease (AD) were largely confined to microglia enhancers, whereas genetic variants for psychiatric disorders were enriched in neuronal enhancers. Additionally, I identified a microglia-specific enhancer at the BIN1 locus that harbors AD-risk variants; BIN1 is an AD-risk gene that has largely been studied in neurons. Deletion of the microglia-specific BIN1 enhancer substantially reduced BIN1 expression in microglia and not in neurons or astrocytes. Overall, this work has revised the gene repertoire influenced by noncoding AD-risk variants and has revealed the likely cell types in which they function.
Medical Center | K307 (3-6407)
Host: Department of Neuroscience - Faculty Search Committee